The present invention relates to formulations comprising highly fluorinated or perfluorinated compounds, referred to generally as fluorocarbons. It relates particularly to fluorocarbon emulsion formulations that form emulsions having superior emulsion stability and controlled particle sizes.
Fluorocarbon compounds and their formulations have numerous applications in human and veterinary medicine as therapeutic and diagnostic agents. Fluorocarbons have many potential applications in the biomedical field, as blood substitutes, or more generally, as carriers in applications wherein oxygen must be supplied to organs and tissues, for example, in the treatment of cardio- and cerebrovascular disease, angioplasty, in organ preservation and in cancer therapy. Fluorocarbon formulations are also useful in diagnostic procedures, for example as contrast agents, and in the field of veterinary therapy (Riess, J. G., Hemocompatible Materials and Devices: Prospectives Towards the 21st Century, Technomics Publ. Co, Lancaster, Pa, USA, Chap 14 (1991); Vox Sanquinis., Vol. 61:225-239 (1991). One commercial biomedical fluorocarbon emulsion, Fluosol(copyright), (Green Cross Corp., Osaka, Japan), is presently used, for example, as an oxygen carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information, Series no 5 and 7, 1981).
The dispersed phase of fluorocarbon emulsions must have a stable particle size to be suitable for biomedical use. One of the drawbacks of the Fluosol emulsion is its low stability; the particle size of fluorocarbon emulsions such as Fluosol(copyright) can be maintained only if they are transported and stored in the frozen state. The frozen emulsions are then defrosted and mixed with two annex solutions before use. These storage requirements seriously limit the field of application of Fluosol. Although more stable fluorocarbon emulsions are being developed (Oxygent(copyright) and Imagent(copyright), Alliance Pharmaceutical Corp., San Diego, Calif.), it is desirable to have fluorocarbon emulsions that are stable enough to store for long periods without refrigeration. Such storage stability would extend the use of fluorocarbons beyond medical facilities in order to meet, for example, the requirements of the army and civil defense. It is also desirable to control particle sizes to adapt the emulsion characteristics to specific applications.
Fluorocarbons are oily substances that are immiscible with water, and therefore fluorocarbon-in-water emulsions, such as Fluosol(copyright) and Oxygent(copyright), are presently prepared using lecithins and/or poloxamers of the Pluronic F-68(copyright) type as surfactants to disperse the fluorocarbon and stabilize the emulsion. Surfactants are commonly amphiphilic compounds having a hydrophobic end region and a hydrophilic end region. Lecithins have a hydrophobic end region comprising a hydrocarbon groups which have a low affinity for fluorocarbons. It is desirable to improve the affinity of the surfactant film for the fluorocarbon phase and to reduce the interfacial tension between the fluorocarbon and aqueous phases. (Riess, J.G., Comptes Rendus du 2xc3xa8me Congrxc3xa8s Mondial des Agents de Surface (Paris, May 1988), ASPA 4:256-263 (1988)).
Several strategies can be employed to overcome this disadvantage:of the emulsifying surfactants described. One approach is to develop more effective surfactants, for example, those having a hydrophobic end which is fluorophilic, for use in the preparation of classic emulsions. Efforts in this direction have led to new fluorinated surfactants such as those described in the documents EP-A- 0 255 443, EP-A-A 0 311 473 and WO 90/15807.
Another strategy is to prepare microemulsions, i.e., preparations of compounds which organize themselves spontaneously into dispersed systems (H. L. Rosano and W. E. Gerbacia, U.S. Pat. No. 3,778,381, Dec. 11, 1973; and G. Mathis, J. J. Delpuech, FR-A-2 515 198, 3.29.1983). In an example of a microemulsion described by Cecutti et al., Eur. J. Med. Chem., 24, 485-492 (1989), the dispersed phase is itself totally constituted of mixed hydrocarbon/fluorocarbon molecules. However, this strategy is not generally applicable to fluorocarbons, particularly those of the examples described in the present invention. Moreover, it is still totally uncertain whether the intravenous administration of microemulsions is safe. To our knowledge, no example of such administration exists in human medicine, whereas the classical emulsions, such as the lipidic emulsions for parenteral nutrition are abundantly used.
It would be advantageous to be able to emulsify any fluorocarbon chosen solely on the basis of its own advantageous properties and its efficacy, without regard to the problem of emulsification. For example, it would be advantageous to be able to prepare stable emulsions of perfluorooctyl bromide (PFOB, Perflubron(copyright), Alliance Pharmaceutical Corp., La Jolla, Calif.) on account of its radiopacity, and of its potential as a contrast agent in diagnostics. It would also be advantageous to set the particle size in the emulsion at a value chosen a priori.
The invention comprises preparations of dispersions, emulsions, and gels comprising a highly fluorinated compound or fluorocarbon, a surfactant, a lipophilic/fluorophilic organic compound, and an aqueous phase, methods of manufacturing the preparations, and their uses. The preparations of the invention comprise an amphiphilic organic fluorophilic-lipophilic compound of the formula RF1xe2x80x94Wxe2x80x94RH1 wherein RF1 is a fluorinated hydrocarbon radical and RH1 is a hydrocarbon radical as defined herein and W is absent or is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or a hydrocarbon group or a hydrocarbon group having fluorinated regions as defined herein.
The lipophilic/fluorophilic compound of the invention can be a branched chain structure comprising hydrocarbon groups and fluorinated hydrocarbon groups, as for example, formulas (II) and (III). The fluorinated hydrocarbon groups of the compound can be further substituted by Br and Cl in addition to F. In a preferred embodiment of the invention, the lipophilic/fluorophilic compound is of the formula
CF3(CF2)t1xe2x80x94(CH2)t2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)yxe2x80x94CH3
wherein t1=2 to 11, t2=0 or 1 to 6 and y=1 to 15.
The lipophilic/fluorophilic compound is advantageously constituted of one or more essentially hydrocarbon fragments of the formula (II) described below and one or more highly fluorinated fragments, typical examples of such compounds being the molecules CF3(CF2)t(CH2)yCH3 or
CF3(CF2)t1xe2x80x94(CH2)t2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)yxe2x80x94CH3
The preparations of the invention further comprise a surfactant selected from a lecithin, a lecithin analog, or the perfluoroalkylated surfactants. The proportions of the components of the preparations are preferably from about 10 to 130% weight/volume of a fluorocarbon-containing phase; from 0.05 to 10% weight/volume of a surfactant; and from about 0.1 to 50% weight/volume of the fluorophilic/lipophilic compound in a suitable aqueous phase.
The emulsions can further comprise any additive suitable to enhance the purpose of the formulation, such as mineral salts, buffers, pharmaceuticals, nutrients, or diagnostic agents. The fluorocarbon can be any suitable fluorocarbon compound, but preferably those molecular species disclosed herein.
The preparations of the invention are prepared by adding an appropriate quantity of the fluorophilic/lipophilic compound to the fluorocarbon or to the aqueous phase prior to emulsification to achieve the desired final concentration of the compound in the emulsion. The addition of the fluorophilic/lipophilic compound acts to bring the emulsion particles to a desired size more rapidly, and to stabilize the emulsion against changes in particle size on storage. The stabilizing effect is relatively independent of storage temperature.
The preparations can have various forms: dispersions, emulsions or gels, and can be used for various purposes, as oxygen carriers, drug carriers or as contrast agents.